The present invention relates to bicyclic nitrogen heterocycles. More particularly, the invention is concerned with alkylamino-substituted dihydropyrimido-[4,5-d]pyrimidinone derivatives, a process for their manufacture and pharmaceutical preparations containing them.
Mitogen-activated protein kinases (MAP) are a family of proline-directed serine/threonine kinases that activate their substrates by dual phosphorylation. The kinases are activated by a variety of signals including nutritional and osmotic stress, UV light, growth factors, endotoxin and inflammatory cytokines. One group of MAP kinases is the p38 kinase group which includes various isoforms (e.g., p38xcex1, p39xcex2 and p38xcex3). The p38 kinases are responsible for phosphorylating and activating transcription factors as well as other kinases, and are themselves activated by physical and chemical stress, pro-inflammatory cytokines and bacterial lipopolysaccharide.
More importantly, the products of the p38 phosphorylation have been shown to mediate the production of inflammatory cytokines, including TNF and IL-1, and cyclooxygenase-2. Each of these cytokines has been implicated in numerous disease states and conditions. For example, TNF-xcex1 is a cytokine produced primarily by activated monocytes and macrophages. Its excessive or unregulated production has been implicated as playing a causative role in the pathogenesis of rheumatoid arthritis. More recently, inhibition of TNF production has been shown to have broad application in the treatment of inflammation, inflammatory bowel disease, multiple sclerosis and asthma.
TNF has also been implicated in viral infections, such as HIV, influenza virus, and herpes virus including herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others.
Similarly, IL-1 is produced by activated monocytes and macrophages, and plays a role in many pathophysiological responses including rheumatoid arthritis, fever and reduction of bone resorption.
The inhibition of these cytokines by inhibition of the p38 kinase is of benefit in controlling, reducing and alleviating many of these disease states.
In one aspect, the present invention provides compounds represented by the formula: 
in which:
the subscript n represents an integer of from 0 to 3, preferably 1 or 2;
R1 represents hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl or aralkyl;
each R2, when present, independently represents alkyl, halo, heteroalkyl, or vinyl;
R3 represents heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylcarbonyl, heterosubstituted cycloalkyl, heterosubstituted cycloalkylalkyl, heterosubstituted cycloalkylalkenyl, heterosubstituted cycloalkylalkynyl, heteroalkylsubstituted cycloalkyl, heterocyclyl, heterocyclylalkyl, arylheteroalkyl, heteroarylheteroalkyl, -(alkylene)-C(O)R31 or -(heteroalkylene)-C(O)R31;
wherein R31 represents alkyl, haloalkyl, hydroxy, alkoxy, amino, monsubstituted amino, disubstituted amino, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
and their pharmaceutically acceptable salts.
In another aspect, the present invention provides compositions comprising a pharmaceutically acceptable excipient and a compound of formula I, above.
In yet another aspect, the present invention provides methods of preparing the compounds described above. Briefly, the methods involve either:
(a) treating a compound of formula II 
xe2x80x83wherein n, R2 and R3 have the meanings provided in claim 1, with the proviso that any interfering reactive group present is optionally in protected form, and L is a leaving group,
with an amine of formula III
R1xe2x80x94NH2xe2x80x83xe2x80x83(III)
wherein R1 has the meaning provided with reference to formula I above, with the proviso that any interfering reactive group present is optionally in protected form, and where required, deprotecting any protected reactive groups. or
(b) treating a compound of formula IV 
xe2x80x83wherein R1, n, and R2 have the meanings provided for formula I, with the proviso that any interfering reactive group present is optionally in protected form,
with an alkylating agent of formula V
R3xe2x80x94Xxe2x80x83xe2x80x83(V)
wherein R3 has the meaning provided with reference to formula I, and X is a leaving group or a hydroxy group that is activated during the reaction, with the proviso that any interfering reactive group present is optionally in protected form, and where required, deprotecting any protected reactive groups.
The compounds of formula I and their aforementioned salts are inhibitors of protein kinases, and exhibit surprisingly effective activity against p38 in vivo. Interestingly, the compounds of formula I do not exhibit activity against the T-cell tyrosine kinase p56lck at levels below about 10 xcexcM. The compounds can be used for the treatment of diseases mediated by the pro-inflammatory cytokines such as TNF and IL-1.
Accordingly, the present invention provides methods for the treatment of p38 mediated diseases or conditions in which a therapeutically effective amount of a compound of formula I is administered to a subject in need of such treatment.
In still another aspect, the present invention provides methods of preparing medicaments useful for the treatment of the p38 mediated diseases and conditions.
Abbreviations and Definitions
As used herein:
xe2x80x9cAlkylxe2x80x9d means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl, and the like.
xe2x80x9cAlkylenexe2x80x9d means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
xe2x80x9cAlkenylxe2x80x9d means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.
xe2x80x9cAlkynylxe2x80x9d means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynyl, propynyl, and the like.
xe2x80x9cCycloalkylxe2x80x9d refers to a saturated monovalent cyclic hydrocarbon radical of three to seven ring carbons. The cycloalkyl may be optionally substituted independently with one, two, or three substituents selected from alkyl, optionally substituted phenyl, or xe2x80x94C(O)R (where R is hydrogen, alkyl, haloalkyl, amino, monsubstituted amino, disubstituted amino, hydroxy, alkoxy, or optionally substituted phenyl). More specifically, the term cycloalkyl includes, for example, cyclopropyl, cyclohexyl, phenylcyclohexyl, 4-carboxycyclohexyl, 2-carboxamidocyclohexyl, 2-dimethylaminocarbonyl-cyclohexyl, and the like.
xe2x80x9cCycloalkenylxe2x80x9d means an unsaturated non-aromatic monovalent cyclic hydrocarbon radical of three to seven ring carbons. Representative examples include cyclohexenyl and cyclopentenyl.
xe2x80x9cCycloalkylalkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is a cycloalkyl group as defined herein, e.g., cyclopropylmethyl, cyclohexylpropyl, 3-cyclohexyl-2-methylpropyl, and the like.
xe2x80x9cAcylxe2x80x9d means the group xe2x80x94C(O)Rxe2x80x2, where Rxe2x80x2 is alkyl, haloalkyl, heteroalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
xe2x80x9cAlkoxyxe2x80x9d, xe2x80x9caryloxyxe2x80x9d, xe2x80x9caralkyloxyxe2x80x9d, or xe2x80x9cheteroaralkyloxyxe2x80x9d means a radical xe2x80x94OR where R is an alkyl, aryl, aralkyl, or heteroaralkyl respectively, as defined herein, e.g., methoxy, phenoxy, pyridin-2-ylmethyloxy, benzyloxy, and the like.
xe2x80x9cHaloxe2x80x9d or xe2x80x9cHalogen,xe2x80x9d means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.
xe2x80x9cHaloalkylxe2x80x9d means alkyl substituted with one or more same or different halo atoms, e.g., xe2x80x94CH2Cl, xe2x80x94CF3, xe2x80x94CH2CF3, xe2x80x94CH2CCl3, and the like, and further includes those alkyl groups such as perfluoroalkyl in which all hydrogen atoms are replaced by fluorine atoms.
xe2x80x9cHydroxyalkylxe2x80x9d means an alkyl radical as defined herein, substituted with one or more, preferably one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group. Representative examples include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxy-butyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-(hydroxymethyl)-2-hydroxyethyl. Accordingly, as used herein, the term xe2x80x9chydroxyalkylxe2x80x9d is used to define a subset of heteroalkyl groups.
xe2x80x9cMonosubstituted aminoxe2x80x9d means a radical xe2x80x94NHR where R is alkyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocyclyl, or heterocyclylalkyl, e.g., methylamino, ethylamino, phenylamino, benzylamino, and the like.
xe2x80x9cDisubstituted aminoxe2x80x9d means a radical xe2x80x94NRRxe2x80x2 where R and Rxe2x80x2 are, independently of each other, alkyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocyclyl, or heterocyclylalkyl, or R and Rxe2x80x2 together with the nitrogen atom to which they are attached form a heterocyclyl ring. Representative examples include, but are not limited to, dimethylamino, methylethylamino, di(1-methyl-ethyl)amino, piperazin-1-yl, and the like.
xe2x80x9cArylxe2x80x9d means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms which is substituted independently with one or more substituents, preferably one, two, or three substituents selected from alkyl, haloalkyl, heteroalkyl, halo, nitro, cyano, methylenedioxy, ethylenedioxy, cycloalkyl, optionally substituted phenyl, heteroaryl, haloalkoxy, optionally substituted phenoxy, heteroaryloxy, xe2x80x94COR (where R is alkyl or optionally substituted phenyl), xe2x80x94(CRxe2x80x2Rxe2x80x3)nxe2x80x94COOR (where n is an integer from 0 to 5, Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl) or xe2x80x94(CRxe2x80x2Rxe2x80x3)nxe2x80x94CONRaRb (where n is an integer from 0 to 5, Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or alkyl, and Ra and Rb are, independently of each other, hydrogen, alkyl, cycloalkyl or cycloalkylalkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a heterocyclyl ring). More specifically the term aryl includes, but is not limited to, phenyl, 1-naphthyl, and 2-naphthyl, and the derivatives thereof.
xe2x80x9cAralkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is an aryl group as defined herein, e.g., benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like.
xe2x80x9cAralkenylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkenylene group and Rb is an aryl group as defined herein, e.g., 3-phenyl-2-propenyl, and the like.
xe2x80x9cArylheteroalkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an heteroalkylene group and Rb is an aryl group as defined herein, e.g., 2-hydroxy-2-phenylethyl, 2-hydroxy-1-hydroxymethyl-2-phenylethyl, and the like.
xe2x80x9cOptionally substituted phenylxe2x80x9d means a phenyl ring which is optionally substituted independently with one or more substituents, preferably one or two substituents selected from alkyl, haloalkyl, heteroalkyl, halo, nitro, cyano, methylenedioxy, ethylenedioxy, cycloalkyl, cycloalkylalkyl, xe2x80x94COR (where R is alkyl or optionally substituted phenyl, xe2x80x94(CRxe2x80x2Rxe2x80x3)nxe2x80x94COOR (where n is an integer from 0 to 5, Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl), or xe2x80x94(CRxe2x80x2Rxe2x80x3)nxe2x80x94CONRaRb (where n is an integer from 0 to 5, Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or alkyl, and Ra and Rb are, independently of each other, hydrogen, alkyl, cycloalkyl or cycloalkylalkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a heterocyclyl ring).
xe2x80x9cHeteroarylxe2x80x9d means a monovalent monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring is optionally substituted independently with one or more substituents, preferably one or two substituents, selected from alkyl, haloalkyl, heteroalkyl, halo, nitro, cyano, cycloalkyl, cycloalkylalkyl, xe2x80x94COR (where R is alkyl or optionally substituted phenyl, xe2x80x94(CRxe2x80x2Rxe2x80x3)nxe2x80x94COOR (where n is an integer from 0 to 5, Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl), or xe2x80x94(CRxe2x80x2Rxe2x80x3)nxe2x80x94CONRaRb (where n is an integer from 0 to 5, Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or alkyl, and Ra and Rb are, independently of each other, hydrogen, alkyl, cycloalkyl or cycloalkylalkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a heterocyclyl ring). More specifically the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl, and the derivatives thereof.
xe2x80x9cHeteroaralkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is a heteroaryl group as defined herein, e.g., pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.
xe2x80x9cHeteroaralkenylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkenylene group and Rb is a heteroaryl group as defined herein, e.g., 3-(pyridin-3-yl)propen-2-yl, and the like.
xe2x80x9cHeterocyclylxe2x80x9d means a saturated or unsaturated non-aromatic cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from NR (where R is independently hydrogen or alkyl), O, or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group. The heterocyclyl ring may be optionally substituted independently with one, two, or three substituents selected from alkyl, haloalkyl, heteroalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, monosubstituted amino, disubstituted amino, xe2x80x94COR (where R is alkyl or optionally substituted phenyl), xe2x80x94(CRxe2x80x2Rxe2x80x3)nxe2x80x94COOR (n is an integer from 0 to 5, Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl), or xe2x80x94(CRxe2x80x2Rxe2x80x3)nxe2x80x94CONRaRb (where n is an integer from 0 to 5, Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or alkyl, and Ra and Rb are, independently of each other, hydrogen, alkyl, cycloalkyl or cycloalkylalkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a heterocyclyl ring). More specifically the term heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidino, N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl, 3-pyrrolidino, morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, , pyrrolinyl, imidazolinyl, and the derivatives thereof.
xe2x80x9cHeterocyclylalkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is a heterocyclyl group as defined herein, e.g., tetrahydropyran-2-ylmethyl, 4-methylpiperazin-1-ylethyl, 3-piperidinylmethyl, and the like.
xe2x80x9cHeteroalkylxe2x80x9d means an alkyl radical as defined herein with one, two or three substituents independently selected from xe2x80x94ORa, NRbRc, and xe2x80x94S(O)nRd (where n is an integer from 0 to 2). Ra is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxycarbonyl, aryloxycarbonyl, carboxamido, or mono- or di-alkylcarbamoyl. Rb is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl. Rc is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, alkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, carboxamido or mono- or di-alkylcarbamoyl. Rd is hydrogen (provided that n is 0), alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, amino, monsubstituted amino, disubstituted amino, or hydroxyalkyl. Representative examples include, for example, 2-methoxyethyl, benzyloxymethyl, thiophen-2-ylthiomethyl, 2-hydroxyethyl, and 2,3-dihydroxypropyl.
xe2x80x9cHeteroalkylenexe2x80x9d means a linear saturated divalent hydrocarbon radical of one to six carbons or a branched saturated hydrocarbon radical of three to six carbon atoms with one, two or three substituents independently selected from xe2x80x94ORa, xe2x80x94NRbRc, and xe2x80x94S(O)nRd (where n is an integer from 0 to 2) where, Ra, Rb, Rc, and Rd are as defined herein for a heteroalkyl radical. Examples include, 2-hydroxyethan-1,1-diyl, 2-hydroxypropan-1,1-diyl and the like.
xe2x80x9cHeterosubstituted cycloalkylxe2x80x9d means a cycloalkyl group wherein one, two, or three hydrogen atoms are replaced by substituents independently selected from the group consisting of hydroxy, alkoxy, amino, monsubstituted amino, disubstituted amino, or xe2x80x94SOnR (where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, amino, monsubstituted amino, disubstituted amino, or hydroxyalkyl). Examples include 4-hydroxycyclohexyl, 2-aminocyclohexyl,
xe2x80x9cHeteroalkylsubstituted cycloalkylxe2x80x9d means a cycloalkyl group wherein one, two, or three hydrogen atoms are replaced independently by heteroalkyl groups. Examples include 1-hydroxymethyl-cyclopent-1-yl, 2-hydroxymethyl-cyclohex-2-yl and the like.
xe2x80x9cLeaving groupxe2x80x9d has the meaning conventionally associated with it in synthetic organic chemistry i.e., an atom or group capable of being displaced by a nucleophile and includes halo (such as chloro, bromo, iodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g. acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy, trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy), methoxy, N,O-dimethylhydroxylamino, and the like.
xe2x80x9cPharmaceutically acceptable excipientxe2x80x9d means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. A xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d as used in the specification and claims includes both one and more than one such excipient.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include:
(1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4xe2x80x2-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or
(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
xe2x80x9cPro-drugsxe2x80x9d means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group in a compound of Formula (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula (I), and the like.
xe2x80x9cProtecting groupxe2x80x9d refers to a grouping of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity. Examples of protecting groups can be found in T. W. Greene and P. G. Futs, Protective Groups in Organic Chemistry, (Wiley, 2nd ed. 1991) and Harrison and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wiley and Sons. 1971-1996). Representative amino protecting groups include formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC) and the like. Representative hydroxy protecting groups include those where the hydroxy group is either acylated or alkylated such as benzyl and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease includes:
(1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease,
(2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or
(3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
xe2x80x9cA therapeutically effective amountxe2x80x9d means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
Compounds
In one aspect, the present invention provides compounds represented by the formula: 
In formula (I), the symbol R1 represents a hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, or aralkyl group.
In preferred embodiments, R1 is alkyl, cycloalkyl, or aralkyl, more preferably alkyl or cycloalkyl. In certain preferred embodiments, R1 is a branched alkyl group in which the carbon atom attached to the nitrogen atom is a tetrahedral carbon atom, preferably having 0 or 1 attached hydrogen atoms. For example, R1 will preferably be 2-methyl-2-propyl, 2-propyl, cyclohexyl, 1-methylcyclohexyl, and the like.
Returning to formula I, the symbol R2 represents alkyl, halo, heteroalkyl or vinyl and can be attached to the phenyl ring at any of the remaining five valences otherwise occupied by hydrogen. The subscript n is an integer of from 0 to 3, indicating that the phenyl ring is substituted by from zero to three R2 groups. For those embodiments in which two or three R2 groups are present, each can be independent of the other(s). In preferred embodiments, n is 1 or 2 and each R2 is halo or alkyl, more preferably halo. Still further preferred are those embodiments in which xe2x80x94(R2)n represents 2-halo or 2,6-dihalo, more preferably 2-chloro or 2,6-dichloro.
The symbol R3 represents heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylcarbonyl, heterosubstituted cycloalkyl, heterosubstituted cycloalkylalkyl, heterosubstituted cycloalkylalkenyl, heterosubstituted cycloalkylalkynyl, heteroalkylsubstituted cycloalkyl, heterocyclyl, heterocyclylalkyl, arylheteroalkyl, heteroarylheteroalkyl, -(alkylene)-C(O)R31 or -(heteroalkylene)-C(O)R31; wherein R31 represents alkyl, haloalkyl, hydroxy, alkoxy, amino, monsubstituted amino, disubstituted amino, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl.
In preferred embodiments, R3 is selected from heteroalkyl, heterocyclyl and heterosubstituted cycloalkyl. In one group of particularly preferred embodiments, R3 is heteroalkyl, more preferably hydroxyalkyl or alkoxyalkyl. Examples of suitable hydroxyalkyl and alkoxyalkyl groups are 2-methoxyethyl, 2-hydroxyethyl, 1-hydroxy-2-propyl, 2-hydroxy-1-propyl, 1-hydroxy-2-(hydroxymethyl)-3-propyl, 1,3-dihydroxy-2-propyl, 1,3-dimethoxy-2-propyl, 1-methoxy-2-(methoxymethyl)-3-propyl, 2,3-dihydroxy-1-propyl, 3,4-dihydroxy-1-cyclopentyl, and the like.
In another group of particularly preferred embodiments, R3 is heterocyclylalkyl. Examples of suitable heterocyclylalkyl groups include 2-(N-piperidinyl)-ethyl, 2-(N-(2-pyrrolidinonyl))ethyl, and the like.
In yet another group of particularly preferred embodiments, R3 is -(alkylene)-C(O)R31; wherein R31 is hydroxy, amino, methylamino, dimethylamino, methyl, and the like. More preferably the alkylene portion is ethylene or propylene.
In addition to the compounds described above, the present invention includes all pharmaceutically acceptable salts of those compounds along with prodrug forms of the compounds and all isomers whether in a pure chiral form or a racemic mixture or other form of mixture.
Still further, combinations of the preferred groups described above will form other preferred embodiments. For example, in one group of particularly preferred embodiments R1 is alkyl or cycloalkyl, R2 is halo, R3 is heteroalkyl or -(alkylene)-C(O)R31; and n is 1 or 2.
Processes for Preparing the Compounds
The compounds of the present invention can be prepared by a variety of methods, using procedures well-known to those of skill in the art. For example, in one embodiment, the compounds are prepared using methods similar to those provided in co-pending U.S. S No. 60/160,804, filed Oct. 21, 1999, and U.S. S No. 60/213,718, filed Jun. 22, 2000 (Bicyclic Nitrogen Heterocycles, and U.S. S Nos. 60/160,803, and 60/213,743, filed Jun. 22, 2000 (Heteroalkylamino-Substituted Bicyclic Nitrogen Heterocycles) filed Oct. 21, 1999 and outlined in Scheme 1. 
Treatment of a compound of formula Ia with a primary amine (R3xe2x80x94NH2) provides a compound of formula Ib. This reaction is conveniently carried out in a solvent which is inert under the reaction conditions, preferably an open-chain or cyclic ether (such as tetrahydrofuran), a halogenated aliphatic hydrocarbon, especially dichloromethane, an optionally halogenated aromatic hydrocarbon, a formamide or a lower alkanol. Suitably, the reaction is carried out at about xe2x88x9220xc2x0 C. to about 120xc2x0 C.
Reduction of a compound of formula Ib provides an alcohol of formula Ic. This reduction is typically carried out using lithium aluminium hydride in a manner well known to those of skill in the art (e.g. in a solvent which is inert under the conditions of the reduction, preferably an open-chain or cyclic ether, especially tetrahydrofuran, at about xe2x88x9220xc2x0 C. to about 70xc2x0 C., preferably at about 0xc2x0 C. to about room temperature).
Oxidation of an alcohol of formula Ic in the next step provides a carboxaldehyde of formula Id. The oxidation is typically carried out with manganese dioxide, although numerous other methods can also be employed (see, for example, Advanced Organic Chemistry, 4th Ed., March, John Wiley and Sons, New York (1992)). Depending on the oxidating agent employed, the reaction is carried out conveniently in a solvent which is inert under the specific oxidation conditions, preferably a halogenated aliphatic hydrocarbon, especially dichloromethane, or an optionally-halogenated aromatic hydrocarbon. Suitably, the oxidation is carried out at about 0xc2x0 C. to about 60xc2x0 C.
Reaction of a carboxaldehyde of formula Id with a substituted aniline to provide a compound of formula Ie. This reaction may be carried out in the presence of an acid, e.g. an aromatic sulfonic acid, preferably 4-toluenesulfonic acid, with azeotropic removal of the water formed during the reaction. Conveniently, the reaction is carried out in a solvent which is inert under the reaction conditions, preferably an aromatic hydrocarbon, especially toluene, or an optionally halogenated aromatic hydrocarbon, and at a temperature of about 70xc2x0 C. to about 150xc2x0 C., especially at the reflux temperature of the solvent to assist in the noted azeotropic removal of water.
Reduction of a compound of formula Ie to give a compound of formula If can be carried out using, for example, sodium borohydride, lithium aluminium hydride or sodium triacetoxyborohydride under conditions well known to those of skill in the art. Preferably, the compound of formula Ie is not purified, but rather the reaction mixture in which it is prepared is concentrated and the concentrate obtained is taken up in a solvent which is inert under the conditions of the reduction, preferably an open-chain or cyclic ether, especially tetrahydrofuran or an optionally halogenated aromatic hydrocarbon or a lower alkanol, and then treated with an aforementioned reducing agents. The reduction is suitably carried out at about 0xc2x0 C. to about 100xc2x0 C., preferably at about 0-25xc2x0 C.
Cyclization of a compound of formula If provides a bicyclic nitrogen heterocycle of formula Ig. The cyclization can be effected by reaction of If with phosgene or trichloromethyl chloroformate (or phosgene equivalent), conveniently in the presence of a tertiary organic base, preferably a tri(lower alkyl)amine, especially triethylamine. More particularly, the cyclization is carried out in a solvent which is inert under the conditions of the reaction, preferably an open-chain or cyclic ether, especially tetrahydrofuran, an optionally halogenated aromatic hydrocarbon or a halogenated aliphatic hydrocarbon. Conveniently, the reaction is carried out at about xe2x88x9220xc2x0 C. to about 50xc2x0 C., preferably at about 0xc2x0 C. to about room temperature.
Oxidation of Ig with 3-chloroperbenzoic acid provides a sulfone (Ih) which can be converted to a variety of target compounds. Typically the oxidation of Ig is carried out in a solvent which is inert under the conditions of the oxidation, preferably a halogenated aliphatic hydrocarbon, especially chloroform or dichloromethane, and at about xe2x88x9220xc2x0 C. to about 50xc2x0 C., preferably about 0xc2x0 C. to about room temperature.
Finally, treatment of Ih with an amine (R1xe2x80x94NH2) provides the target compounds of formula I. The reaction can be carried out in the presence or absence of solvent. Conveniently, the reaction is carried out at temperatures of from about 0xc2x0 C. to about 200xc2x0 C., more preferably about room temperature to about 150xc2x0 C.
Accordingly, the present invention provides a method of preparing compounds of formula I, by treating a compound of general formula Ii with an amine (R1xe2x80x94NH2). 
In compound Ii, the symbols R2, R3 and the subscript n have the meanings provided above with reference to formula I. The letter L represents a leaving group which can be a halogen, a lower alkanesulfonyl group (e.g., methanesulfonyl or trifluoromethanesulfonyl) or an aromatic sulfonyl group (e.g., benzenesulfonyl or 4-toluenesulfonyl). Other suitable leaving groups are known to those of skill in the art and can be found in, for example, Advanced Organic Chemistry, 4th Ed., March; John Wiley and Sons, New York (1992). Suitable amines (R1xe2x80x94NH2) are those in which R1 represents any of the R1 groups noted for formula I.
In a preferred embodiment, the bicyclic nitrogen heterocycle can be constructed and R3 can be introduced at a later stage of synthesis as shown in Scheme 2. 
Compound IIa, the starting material in Scheme 2, can be prepared from commercially available ethyl 4-amino-2-mercapto-pyrimidine-5-carboxylate. Briefly, treatment of the mercapto compound with a suitable alkylating agent (Rxe2x80x94X) provides a compound of formula Ib (R3=H). Conversion of Ib (R3=H) to IIa can follow the steps provided in Scheme I.
Cyclization of IIa provides a bicyclic nitrogen heterocycle of formula IIb. The cyclization can be effected by reaction of IIa with phosgene or trichloromethyl chloroformate (or phosgene equivalent), typically in the presence of a tertiary organic base, preferably a tri(lower alkyl)amine, especially triethylamine. More particularly, the cyclization is carried out in a solvent which is inert under the conditions of the reaction, preferably an open-chain or cyclic ether, especially tetrahydrofuran, an optionally halogenated aromatic hydrocarbon or a halogenated aliphatic hydrocarbon. Conveniently, the reaction is carried out at about xe2x88x9220xc2x0 C. to about 50xc2x0 C., preferably at about 0xc2x0 C. to about room temperature.
Introduction of an R3 group to provide a compound of formula IIc can be accomplished under a variety of conditions. For example, IIb can be treated with alkali metal hydride, especially sodium hydride, and subsequent reaction with a compound of the general formula R3xe2x80x94L, wherein R3 has any of the values accorded to R3 hereinbefore except hydrogen, aryl or heteroaryl and L represents a leaving group (e.g., halo, methanesulfonate, toluenesulfonate, trifluoromethanesulfonate, and the like). The N-substitution is conveniently carried out in a solvent which is inert under the reaction conditions, preferably a formamide, especially N-methylpyrrolidinone or dimethylformamide, an open-chain or cyclic ether or an optionally halogenated aromatic hydrocarbon. Suitably, the reaction is carried out at about 50xc2x0 C. to about 200xc2x0 C., preferably at about 50xc2x0 C. to about 150xc2x0 C. Alternatively, the alkylation may be carried out with an inorganic base such as potassium carbonate in a formamide solvent such as N-methylpyrrolidinone temperatures from about 0xc2x0 C. to about 25xc2x0 C.
An alternative, and preferable method for the introduction of R3 involves alkylation of the pyrimidinone nitrogen under Mitsonobu conditions. In this method, an alcohol of the general formula R3xe2x80x94OH is combined with a compound of general formula IIb in the presence of, for example, triphenylphosphine and diethyl azodicarboxylate or diphenylpyridyl phosphine and t-butylazodicarboxylate (See, Tetrahedron Lett., 40: 4497-4500 (1999). The alkylation is conveniently carried out in a solvent which is inert under the reaction conditions, preferably an open-chain or cyclic ether, at temperatures of about xe2x88x9220xc2x0 C. to about 100xc2x0 C., preferably at about 0xc2x0 C. to about 30xc2x0 C. (or room temperature). As with other alkylation methods, primary and secondary alcohols are the most suitable for reaction under these conditions.
Following the introduction of R3, the oxidation and displacement steps (to introduce R1xe2x80x94NHxe2x80x94) can be accomplished as outlined above to provide target compounds of formula I.
In alternate routes, IIb may be converted to IId by first alkylating IIb under Mitsunobu conditions to introduce R3, followed by oxidation of the sulfide to the corresponding sulfone IId.
In still other embodiments, the compounds can be prepared by reversing the order of alkylation and displacement steps, thereby reversing the order of xe2x80x94R3 and xe2x80x94NHxe2x80x94R1 introduction, shown in Scheme 3. 
Accordingly, a compound of formula IIa can be cyclized to IIb (as initially shown in Scheme 2). Oxidation of IIb to IIIa provides the template for the subsequent displacement and alkylation steps. Thus, treatment of IIIa with R1xe2x80x94NH2 under the conditions described above, provides IIIb, which can be alkylated using R3xe2x80x94L (wherein L has the meaning noted above) or R3xe2x80x94OH under Mitsunobu conditions to provide the target compounds of formula I.
One of skill in the art will understand that certain modifications to the above schemes are contemplated and within the scope of the present invention. For example, certain steps will involve the protection and deprotection of reactive functional groups that are not compatible with particular reaction conditions.
Pharmaceutical Compositions Containing the Compounds
The compounds of formula I and the pharmaceutically acceptable salts of basic compounds of formula I with acids can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered enterally, e.g. orally in the form of tablets, coated tablets, dragxc3xa9es, hard and soft gelatine capsules, solutions, emulsions or suspensions, nasally, e.g. in the form of nasal sprays, or rectally, e.g. in the form of suppositories. However, they may also be administered parenterally, e.g. in the form of injection solutions.
The compounds of formula I and their aforementioned pharmaceutically acceptable salts can be processed with pharmaceutically inert, organic or inorganic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragxc3xa9es and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active ingredient no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
The pharmaceutical preparations can also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain therapeutically valuable substances other than the compounds of formula I and their aforementioned pharmaceutically acceptable salts.
Medicaments which contain a compound of formula I or a pharmaceutically acceptable salt of a basic compound of formula I with an acid in association with a compatible pharmaceutical carrier material are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more of these compounds or salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with a compatible pharmaceutical carrier.
As mentioned earlier, the compounds of formula I and their aforementioned pharmaceutically acceptable salts can be used in accordance with the invention as therapeutically active substances, especially as antiinflammatory agents or for the prevention of graft rejection following transplant surgery. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of administration to adults a convenient daily dosage should be about 0.1 mg/kg to about 100 mg/kg, preferably about 0.5 mg/kg to about 5 mg/kg. The daily dosage may be administered as a single dose or in divided doses and, in addition, the upper dosage limit referred to earlier may be exceeded when this is found to be indicated.
Finally, the use of compounds of formula I and their aforementioned pharmaceutically acceptable salts for the production of medicaments, especially in the treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular disorders, in the treatment of asthma, central nervous system disorders or diabetic complications or for the prevention of graft rejection following transplant surgery, is also an object of the invention.
Methods of Using the Compounds and Compositions
Compounds of formula I would be useful for, but not limited to, the treatment of any disorder or disease state in a human, or other mammal, which is excacerbated or caused by excessive or unregulated TNF and/or IL-1 or p38 kinase production by such mammal. Accordingly, the present invention provides a method of treating a cytokine-mediated disease which comprises administering an effective cytokine-interfering amount of a compound of formula I, or a pharmaceutically acceptable salt or tautomer thereof.
Compounds of formula I would be useful for, but not limited to, the treatment of inflammation in a subject, and for use as antipyretics for the treatment of fever. Compounds of the invention would be useful to treat arthritis, including but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, gouty arthritis and other arthritic conditions. Such compounds would be useful for the treatment of pulmonary disorders or lung inflammation, including adult respiratory distress syndrome, pulmonary sarcoidosis, asthma, silicosis, and chronic pulmonary inflammatory disease. The compounds are also useful for the treatment of viral and bacterial infections, including sepsis, septic shock, gram negative sepsis, malaria, meningitis, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), pneumonia, and herpesvirus. The compounds are also useful for the treatment of bone resorption diseases, such as osteoporosis, endotoxic shock, toxic shock syndrome, reperfusion injury, autoimmune disease including graft vs. host reaction and allograft rejections, cardiovascular diseases including atherosclerosis, thrombosis, congestive heart failure, and cardiac reperfusion injury, renal reperfusion injury, liver disease and nephritis, and myalgias due to infection.
The compounds are also useful for the treatment of influenza, multiple sclerosis, cancer, diabetes, systemic lupus erthrematosis (SLE), skin-related conditions such as psoriasis, eczema, burns, dermatitis, keloid formation, and scar tissue formation. Compounds of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn""s disease, gastritis, irritable bowel syndrome and ulcerative colitis. The compounds would also be useful in the treatment of ophthalmic diseases, such as retinitis, retinopathies, uveitis, ocular photophobia, and of acute injury to the eye tissue. Compounds of the invention also would be useful for treatment of angiogenesis, including neoplasia; metastasis; ophthalmological conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological, but non-malignant, conditions such as hemaginomas, including invantile hemaginomas, angiofibroma of the nasopharynx and avascular necrosis of bone; diabetic nephropathy and cardiomyopathy; and disorders of the female reproductive system such as endometriosis. The compounds of the invention may also be useful for preventing the production of cyclooxygenase-2 and the compounds of this invention are also expected to be useful in the prevention and treatment of cancer, in particular colon cancer. The compounds of this invention are also expected to be useful in the prevention and treatment of Alzheimer""s disease.
Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
The present compounds may also be used in co-therapies, partially or completely, in place of other conventional antiinflammatories, such as together with steroids, cyclooxygenase-2 inhibitors, NSAIDs, DMARDS, immunosuppressive agents, 5-lipoxygenase inhibitors, LTB4 antagonists and LTA4 hydrolase inhibitors.
As used herein, the term xe2x80x9cTNF mediated disorderxe2x80x9d refers to any and all disorders and disease states in which TNF plays a role, either by control of TNF itself, or by TNF causing another monokine to be released, such as but not limited to IL-1, IL-6 or IL-8. A disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disorder mediated by TNF.
As used herein, the term xe2x80x9cp38 mediated disorderxe2x80x9d refers to any and all disorders and disease states in which p38 plays a role, either by control of p38 itself, or by p38 causing another factor to be released, such as but not limited to IL-1, IL-6 or IL-8. A disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to p38, would therefore be considered a disorder mediated by p38.
As TNF-xcex2 has close structural homology with TNF-xcex1 (also known as cachectin), and since each induces similar biologic responses and binds to the same cellular receptor, the synthesis of both TNF-xcex1 and TNF-xcex2 are inhibited by the compounds of the present invention and thus are herein referred to collectively as xe2x80x9cTNFxe2x80x9d unless specifically delineated otherwise.